- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03776656
Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency (ADSL)
Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)
The aim of this study is to evaluate the effectiveness of allopurinol treatment at 12 months on the adaptive and cognitive functioning of patients with adenylosuccinate lyase deficiency (ADSL). The psychiatric evaluation will involve the use of standardized tools prior to initiation of treatment, and will be repeated 6 months and 12 months after the start of treatment.
The decrease in the concentration of SAICAR and S-Ado metabolites, which are markers of adenylosuccinate lyase (ADSL) deficiency, will also be quantified.
Similarly, the efficacy of allopurinol on epileptic seizures for epileptic patients and on electrocardiogram abnormalities will be evaluated secondarily
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Adenylosuccinate lyase deficiency (ADSL) is a rare disorder of purine metabolism whose symptoms are mental retardation, autistic disorders, epilepsy, related to the accumulation of succinylpurines: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S- Ado). The S-Ado / SAICAr ratio in the cerebrospinal fluid (CSF) is correlated with the clinical severity: the cerebral toxicity of SAICAr is incriminated. There is no specific treatment.
Based on the work of Gertrude B. Elion (1988 Nobel Prize in Medicine), who reports that allopurinol (a structural analogue of hypoxanthine) can be a substrate for hypoxanthine phosphoribosyltransferase (HPRT) and thus produce allopurinol ribonucleotides with as a first step in the de novo synthesis of purines, investigators tested the hypothesis that treatment with allopurinol in children with ADSL deficiency would reduce the production of the toxic metabolite SAICAr.
This hypothesis was validated in 3 minor patients with biological and clinical improvement.
So the investigators put the phase II, non-comparative study based on 4 visits to Necker-Enfants malades Hospital or La Pitié-Salpêtrière Hospital: Month 0 (before treatment), Month 3, Month 6 and Month 12 after the start of treatment.
After verification of the inclusion criteria and information of the parents or the patient or guardian, signature of the consent and inclusion of the patient:
- Clinical and neurological evaluation;
- Psychiatric assessment with standardized tests;
- Biological evaluation: determination of urinary and plasma metabolites (SAICAr, S-Ado, ...) Experimental treatment: Allopurinol (Zyloric®) will be administered orally for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Paris, France, 75013
- LA PITIE-SALPETRIERE Hospital, AP-HP
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Paris, France, 75015
- Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Child (minimum age 18 months) or adult with adenylosuccinate lyase; deficiency (ADSL) confirmed by quantification of SAICAr and S-Ado urinary;
Girls / women of childbearing age must:
- have a negative pregnancy test;
- agree to use a reliable method of contraception from the baseline visit to the last dose of study treatment
- Consent of the patient, his parents or his legal representative;
- Beneficiary of social security (affiliated or entitled).
Exclusion Criteria:
- Refusal of the child, his parents or the patient or his representative;
- Allergy known to allopurinol or to one of the constituents of the product (lactose in particular);
- Patients treated with Antipurines (azathioprine, mercaptopurine);
- Patients treated with vidarabine, cytotoxic drugs (eg cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), ciclosporin, or didanosine
- Renal failure characterized by creatinine clearance <80 ml/mn
- Hepatic insufficiency
- Medullary insufficiency but possibly serious
- Breastfeeding
- Pregnancy or wishing to conceive during the study period
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Allopurinol
Oral administration of Allopurinol (Zyloric®) for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure
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Daily oral administration
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale
Time Frame: 12 months
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to assess Efficacy of Allopurinol (Zyloric)® treatment from Baseline : For each scale : Mean : 100 SD : 15
|
12 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Evolution of the Scores of different subdomains Vineland II scale from baseline
Time Frame: at 0, 6 months and 12 months
|
Clinical evolution for developmental and cognitive assessment
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at 0, 6 months and 12 months
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Evolution of the Psycho-Educative Profile (PEP III/R) from baseline
Time Frame: at 0, 12 months
|
Clinical evolution for developmental and cognitive assessment
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at 0, 12 months
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Evolution of the Score ADI-R (Autism Diagnostic Interview-Revised) from baseline
Time Frame: at 0, 12 months
|
Clinical evaluation for autistic symptoms : scale ranges :
better score : 0 (non autistic) - worse score : the higher score is the worst |
at 0, 12 months
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Evolution of the Score ADOS-2 (Autism Diagnostic Observation Schedule 2) from baseline
Time Frame: at 0, 12 months
|
Clinical evaluation for autistic symptoms. Scale ranges :
Autism : total score>12 - Autism Spectrum Disorder : total score >8 Better score : 0 - Worse score : the highest score is the worst |
at 0, 12 months
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Evolution of the Score on Conners hyperactivity Scale
Time Frame: at 0, 6 months and 12 months
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Clinical evolution for behavioral disorders and adaptive functioning Conners Scale for Parents : - Subscales : Behavioural difficulties (items 2-8-14-19-20-27-35-39) : 0 to 24 Learning difficulties (items 10-25-31-37) : 0 to 12 Somatisation (items 32-41-43-44) : 0 to 12 Impulsivity, hyperactivity (items 4-5-11-13): 0 to 12 Anxiety (items 12-16-24-47): 0 to 12 -Hyperactivity index : sum of the items (4-7-11-13-14-25-31-33-37-38) divided by 10 : 0 to 3 Conners Scale for teachers : - Subscales : Behavioural difficulties (items 4-5-6-10-11-12-23-27) : 0 to 24 Impulsivity, hyperactivity (items 1-2-3-8-14-15-16) : 0 to 21 Inattention, passivity (items 7-9-18-20-21-22-26-28) : 0 to 24 -Hyperactivity index (sum of the items 1-5-7-8-10-11-14-15-21-26 divided by 10) : 0 to 3 Better score : 0 - Worse score : the highest score is the worst -Hyperactivity index : Significative if> 1,5 |
at 0, 6 months and 12 months
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Evolution of the Score on ABC scale (Aberrant Behaviour Checklist)
Time Frame: at 0, 6 months and 12 months
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Clinical evolution for behavioral disorders and adaptive functioning scale ranges :
Better score : 0 -Worse score : the highest score is the worst on each scale- there is no total score |
at 0, 6 months and 12 months
|
Evolution of SAICAr levels in the urine
Time Frame: at 0, 6 months and 12 months
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Evolution of the quantity of urinary metabolites from Baseline
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at 0, 6 months and 12 months
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Evolution of S-Ado levels in the urine
Time Frame: at 0, 6 months and 12 months
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Evolution of the quantity of urinary metabolites from Baseline
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at 0, 6 months and 12 months
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Evolution of SAICAr levels in the blood
Time Frame: at 0, 6 months and 12 months
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Evolution of the quantity of plasma metabolites from Baseline
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at 0, 6 months and 12 months
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Evolution of S-Ado levels in the blood
Time Frame: at 0, 6 months and 12 months
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Evolution of the quantity of plasma metabolites from Baseline
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at 0, 6 months and 12 months
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Evolution of the number of seizures from Baseline for epileptic patients
Time Frame: at 0 and 12 months
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at baseline, performing neurological examinations and interrogation
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at 0 and 12 months
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Evolution of antiepileptic treatments from Baseline for epileptic patients
Time Frame: at 0 and 12 months
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at baseline, performing neurological examinations and interrogation
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at 0 and 12 months
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Evolution of electroencephalogram tracing from Baseline for epileptic patients
Time Frame: at 0 and 12 months
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normal/abnormal
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at 0 and 12 months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Pascale De Lonlay, MD, PhD, Assistance Publique - Hôpitaux de Paris
- Study Director: Irène CEBALLOS-PICOT, MD, PhD, Assistance Publique - Hôpitaux de Paris
- Study Director: Laurence ROBEL-GALLI, MD, Assistance Publique - Hôpitaux de Paris
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Metabolic Diseases
- Genetic Diseases, Inborn
- Metabolism, Inborn Errors
- Neurodevelopmental Disorders
- Child Development Disorders, Pervasive
- Autism Spectrum Disorder
- Autistic Disorder
- Purine-Pyrimidine Metabolism, Inborn Errors
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites
- Protective Agents
- Antioxidants
- Free Radical Scavengers
- Gout Suppressants
- Allopurinol
Other Study ID Numbers
- P160902J
- 2017-002155-28 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Adenylosuccinate Lyase Deficiency
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